The long term goal of this project is to contribute to the understanding of the role of K+ channel diversity in the central nervous system (CNS). K+ channels regulate neuronal excitability. They underlie many of the differences in functional properties that characterize specific neurons, contributing to the complexity of neuronal information coding and integration. It is hypothesized that their diversity provides signaling specificity to neuronal circuits and to the actions of neurotransmitters. Mutations in genes encoding K+ channels have been found to cause epilepsy, schizophrenia and autism. This proposal focuses on a subtype of cortical GABAergic inhibitory interneuron known as the fast-spiking (FS) cell, named for its ability to fire sustained trains of action potentials (APs) at remarkably high frequencies. GABAergic interneurons are key components of the cerebral cortex and have essential roles in information processing, plasticity, the generation of cortical rhythms, and in the pathogenesis of seizures. Knowledge of the molecular elements responsible for FS cell function is critical for the manipulation of cortical function to understand physiological and patophysiological conditions and to provide targets for therapeutic drugs. It was recently discovered that K+ channels of the Kv1 subfamily, specifically localized to the axon initial segment (AIS) of FS cells dynamically regulate their activity. The goal of this renewal application is to test the hypothesis that Kv1 channels with specific properties, present at the AIS of FS neurons, control the timing of FS cell-mediated inhibition in the cortex. Experiments will characterize the molecular composition and organization of Kv1 channels at the AIS and their differential regulation of AP generation among neocortical neurons (Aim 1). Experiments will also investigate the role of Kv1 channels in the firing behavior of FS cells in response to biologically relevant stimuli (Aim 2) and the role of Kv1 channels in FS neurons in cortical rhythmic activity and sensory processing (Aim 3). PUBLIC HEALTH RELEVANCE: This project investigates the role of potassium channels in a subtype of neuron in the cerebral cortex known as the fast-spiking cell that is important in the generation of gamma rhythms, sensory perception and the pathogenesis of schizophrenia and autism.